HIV-2 as a model to identify a functional HIV cure

Two HIV virus types exist: HIV-1 is pandemic and aggressive, whereas HIV-2 is confined mainly to West Africa and less pathogenic. Despite the fact that it has been almost 40 years since the discovery of AIDS, there is still no cure or vaccine against HIV. Consequently, the concepts of functional vaccines and cures that aim to limit HIV disease progression and spread by persistent control of viral replication without life-long treatment have been suggested as more feasible options to control the HIV pandemic. To identify virus-host mechanisms that could be targeted for functional cure development, researchers have focused on a small fraction of HIV-1 infected individuals that control their infection spontaneously, so-called elite controllers. However, these efforts have not been able to unravel the key mechanisms of the infection control. This is partly due to lack in statistical power since only 0.15% of HIV-1 infected individuals are natural elite controllers. The proportion of long-term viral control is larger in HIV-2 infection compared with HIV-1 infection. We therefore present the idea of using HIV-2 as a model for finding a functional cure against HIV. Understanding the key differences between HIV-1 and HIV-2 infections, and the cross-reactive effects in HIV-1/HIV-2 dual-infection could provide novel insights in developing functional HIV cures and vaccines

Frequent CXCR4 tropism of HIV-1 subtype A and CRF02_AG during late-stage disease - indication of an evolving epidemic in West Africa

<p>Abstract</p> <p>Background</p> <p>HIV-1 is one of the fastest evolving pathogens, and is distinguished by geographic and genetic variants that have been classified into different subtypes and circulating recombinant forms (CRFs). Early in infection the primary coreceptor is CCR5, but during disease course CXCR4-using HIV-1 populations may emerge. This has been correlated with accelerated disease progression in HIV-1 subtype B. Basic knowledge of HIV-1 coreceptor tropism is important due to the recent introduction of coreceptor antagonists in antiretroviral therapy, and subtype-specific differences regarding how frequently HIV-1 CXCR4-using populations appear in late-stage disease need to be further investigated. To study how frequently CXCR4-using populations appear in late-stage disease among HIV-1 subtype A and CRF02_AG, we evaluated the accuracy of a recombinant virus phenotypic assay for these subtypes, and used it to determine the HIV-1 coreceptor tropism of plasma samples collected during late-stage disease in Guinea-Bissau. We also performed a genotypic analysis and investigated subtype-specific differences in the appearance of CXCR4 tropism late in disease.</p> <p>Results</p> <p>We found that the recombinant virus phenotypic assay accurately predicted HIV-1 coreceptor tropism of subtype A and CRF02_AG. Over the study period (1997-2007), we found an increasing and generally high frequency of CXCR4 tropism (86%) in CRF02_AG. By sequence analysis of the V3 region of our samples we developed a novel genotypic rule for predicting CXCR4 tropism in CRF02_AG, based on the combined criteria of the total number of charged amino acids and net charge. This rule had higher sensitivity than previously described genotypic rules and may be useful for development of future genotypic tools for this CRF. Finally, we conducted a literature analysis, combining data of 498 individuals in late-stage disease, and found high amounts of CXCR4 tropism for all major HIV-1 subtypes (60-77%), except for subtype C (15%).</p> <p>Conclusions</p> <p>The increase in CXCR4 tropism over time suggests an evolving epidemic of CRF02_AG. The results of the literature analysis demonstrate the need for further studies investigating subtype-specific emergence for CXCR4-tropism; this may be particularly important due to the introduction of CCR5-antagonists in HIV treatment regimens.</p

HTLV-1 and HIV-2 Infection Are Associated with Increased Mortality in a Rural West African Community

BACKGROUND: Survival of people with HIV-2 and HTLV-1 infection is better than that of HIV-1 infected people, but long-term follow-up data are rare. We compared mortality rates of HIV-1, HIV-2, and HTLV-1 infected subjects with those of retrovirus-uninfected people in a rural community in Guinea-Bissau. METHODS: In 1990, 1997 and 2007, adult residents (aged ≥15 years) were interviewed, a blood sample was drawn and retroviral status was determined. An annual census was used to ascertain the vital status of all subjects. Cox regression analysis was used to estimate mortality hazard ratios (HR), comparing retrovirus-infected versus uninfected people. RESULTS: A total of 5376 subjects were included; 197 with HIV-1, 424 with HIV-2 and 325 with HTLV-1 infection. The median follow-up time was 10.9 years (range 0.0-20.3). The crude mortality rates were 9.6 per 100 person-years of observation (95% confidence interval 7.1-12.9) for HIV-1, 4.1 (3.4-5.0) for HIV-2, 3.6 (2.9-4.6) for HTLV-1, and 1.6 (1.5-1.8) for retrovirus-negative subjects. The HR comparing the mortality rate of infected to that of uninfected subjects varied significantly with age. The adjusted HR for HIV-1 infection varied from 4.0 in the oldest age group (≥60 years) to 12.7 in the youngest (15-29 years). The HR for HIV-2 infection varied from 1.2 (oldest) to 9.1 (youngest), and for HTLV-1 infection from 1.2 (oldest) to 3.8 (youngest). CONCLUSIONS: HTLV-1 infection is associated with significantly increased mortality. The mortality rate of HIV-2 infection, although lower than that of HIV-1 infection, is also increased, especially among young people

Histopathological alterations in Senegal sole, Solea Senegalensis, from a polluted Huelva estuary (SW, Spain)

As a component of a large research project to evaluate the effects of contaminants on fish health in the field, histopathological studies have been conducted to help establish causal relationship between pollutants (heavy metals and aromatic polycyclic hydrocarbons—PAHs) and histopathological responses in Senegal sole, Solea senegalensis, from an estuary of SW Spain. Heavy metals (As, Zn, Cd, Pb, Cu and Fe) and 16 PAHs (proprietary USEPA) concentrations in water, sediment and tissues (liver and gills) and histopathological alterations in S. senegalensis from three sampling sites of Ria de Huelva estuary during 2004–2006 years have been analysed. The histopathological studies revealed seasonal and spatial differences in the lesion grade of alterations observing the highest lesion grades in fish from Odiel River and autumn season. No significant differences were observed in the alterations prevalence between sampling sites, but significant differences were observed between seasons observing the highest prevalence in autumn season. However, calculated IPAT demonstrated a low–moderate impact of pollutants on health fish. Correlations between histopathological alterations and pollutants analysed were observed being heavy metals the group that presented a major number of correlations with alterations in several organs of S. senegalensis. In evaluating the general health of fish, the use of histopathological studies in recommended for making more reliable assessment of biochemical responses in fish exposed to a variety of environmental stressors. Statistical analysis using semiquantitative data on pathological lesions can help to establish correlation between cause (stressor) and effect (biomarker)

Setting a baseline for global urban virome surveillance in sewage

The rapid development of megacities, and their growing connectedness across the world is becoming a distinct driver for emerging disease outbreaks. Early detection of unusual disease emergence and spread should therefore include such cities as part of risk-based surveillance. A catch-all metagenomic sequencing approach of urban sewage could potentially provide an unbiased insight into the dynamics of viral pathogens circulating in a community irrespective of access to care, a potential which already has been proven for the surveillance of poliovirus. Here, we present a detailed characterization of sewage viromes from a snapshot of 81 high density urban areas across the globe, including in-depth assessment of potential biases, as a proof of concept for catch-all viral pathogen surveillance. We show the ability to detect a wide range of viruses and geographical and seasonal differences for specific viral groups. Our findings offer a cross-sectional baseline for further research in viral surveillance from urban sewage samples and place previous studies in a global perspective

The complex relationship between human immunodeficiency virus infection and death in adults being treated for tuberculosis in Cape Town, South Africa

Background Despite recognised treatment strategies, mortality associated with tuberculosis (TB) remains significant. Risk factors for death during TB treatment have been described but the complex relationship between TB and HIV has not been fully understood. Methods A retrospective analysis of all deaths occurring during TB treatment in Cape Town, South Africa between 2009 and 2012 were done to investigate risk factors associated with this outcome. The main risk factor was HIV status at the start of treatment and its interaction with age, sex and other risk factors were evaluated using a binomial regression model and thus relative risks (RR) are reported. Results Overall in the 93,133 cases included in the study 4619 deaths (5 %) were recorded. Across all age groups HIV-positive patients were more than twice as likely to die as HIV-negative patients, RR = 2.19 (95 % CI: 2.03–2.37). However in an age specific analysis HIV-positive patients 15–24 and 25–34 years old were at an even higher risk of dying than HIV-negative patients, RR = 4.82 and RR = 3.76 respectively. Gender also modified the effect of HIV- with positive women having a higher risk of death than positive men, RR = 2.74 and RR = 1.94 respectively. Conclusion HIV carries an increased risk of death in this study but specific high-risk groups pertaining to the impact of HIV are identified. Innovative strategies to manage these high risk groups may contribute to reduction in HIV-associated death in TB patients

Performance of simultaneous emission-transmission systems for attenuation-corrected SPEct: a method for validation applied to two camera systems

Several commercially available systems for attenuation correction in single photon emission computed tomography (SPECT) based on a transmission scan have been introduced that vary in performance. A test procedure for attenuation correction in SPECT is described and applied to two principally different gamma camera systems (the Siemens Multispect 3 triple-headed system [3HS] and the ADAC Genesys Vertex double-headed system [2HS]). The test procedure was based on geometrically well-defined phantoms. A torso phantom was used to illustrate the attenuation correction methods. The test procedure can be used without detailed knowledge of or access to the algorithms used for attenuation correction. The influence on the transmission measurement of radioactivity in a phantom was higher for the 2HS than for the 3HS. The 3HS produced satisfactory attenuation maps and corrected emission count rates to a constant value independent of phantom density and size. With the 2HS, there was a progressive decrease in the correction of emission count rates with increasing phantom density, and about 30% lower corrected count rates in the large compared with the small phantom. A decrease in measured attenuation coefficients in the vicinity of an emission source was demonstrated in large but not small phantoms. A likely explanation is erroneous correction of downscatter into the transmission energy window. This study demonstrates the need for independent evaluation of systems for attenuation correction in SPECT

A general, extracorporeal immunoadsorption method to increase the tumor-to-normal tissue ratio in radioimmunoimaging and radioimmunotherapy

The aim of this study was to investigate a new extracorporeal immunoadsorption method to improve tumor-to-normal tissue ratios in radioimmunoimaging (RII) and radioimmunotherapy (RIT). We have developed and investigated a general method using biotinylated antibodies and an agarose-avidin column for extracorporeal immunoadsorption. The studies were made in an animal model and extracorporeal immunoadsorption (ECIA) was performed 24 or 48 hr after the injection of 125I-labeled biotinylated antibodies. In athymic rats, heterotransplanted with human malignant melanoma, 90%-95% of the circulating activity was removed with ECIA. The tumor-to-normal tissue ratios at 24 hr was increased 4 times (from 1.2 to 5.1) in the liver, 2.5 times (0.7 to 1.8) in the lung, 4 times (1 to 4) in the kidneys and 4 times (1.4 to 5) in the bone marrow. Whole body activity was reduced by 40%-50%. Tumor-to-organ ratios at 48 hr were increased 3.5 times (from 1.5 to 5.2) in the liver, 2 times (0.9 to 1.7) in the lung, 3 times (1.3 to 3.8) in the kidneys and 4 times (1.4 to 5.5) in the bone marrow. Whole body activity was reduced by 35% when ECIA was performed 48 hr after injection. This study proves that an important reduction in background activity, and thereby an improvement in the tumor-to-background ratio, can be achieved by using this generally applicable, biotin-avidin ECIA method. For RII, the improved ratio increases the possibilities of detecting tumors and metastases in blood-rich organs. For RIT, the procedure may lead to a decreased absorbed dose to bone marrow and other critical organs